Encephalitis

Encephalitis, an inflammation of the brain parenchyma, presents as diffuse and/or focal neuropsychological dysfunction. ^[1] Although it primarily involves the brain, the meninges are frequently involved (meningoencephalitis).

From an epidemiologic and pathophysiologic perspective, encephalitis is distinct from meningitis, though on clinical evaluation both can be present, with signs and symptoms of meningeal inflammation, such as photophobia, headache, or stiff neck. It is also distinct from cerebritis. Cerebritis describes the stage preceding abscess formation and implies a highly destructive bacterial infection of brain tissue, whereas acute encephalitis is most commonly a viral infection with parenchymal damage varying from mild to profound.

Although bacterial, fungal, and autoimmune disorders can produce encephalitis, most cases are viral in origin. The global incidence of encephalitis is 1.5 to 14 per 100,000 population per year. ^{[3, 4]} In the United States, there are approximately 20,000 cases reported each year, ^[5] with herpes simplex virus (HSV) being the most common cause. ^[6] Considering the subacute and chronic encephalopathies, the emergency department (ED) physician is most likely to encounter toxoplasmosis in an immune-compromised host.

The relatively common acute arboviral encephalitides vary widely in epidemiology, mortality, morbidity, and clinical presentation, and no satisfactory treatment exists for these infections. ^[7] However, attempts to distinguish these acute arboviral encephalitides from the treatable acute viral encephalitides due to herpes simplex or varicella are important.

Herpes simplex encephalitis (HSE), which occurs sporadically in healthy and immune-compromised adults is also encountered in neonates infected at birth during vaginal delivery and is potentially lethal if not treated. Varicella-zoster virus encephalitis (VZVE) is life threatening in immune-compromised patients. Swift identification and immediate treatment of HSE or VZVE can be lifesaving. From a risk-benefit standpoint, most authorities recommend initiating ED treatment with acyclovir in any patient whose central nervous system (CNS) presentation is suggestive of viral encephalitis, especially in the presence of fever, encephalopathy, or focal findings, and in all neonates who appear ill for whom a CNS infection is being considered.

West Nile encephalitis

In 1999, a late summer outbreak of West Nile encephalitis (WNE), an arbovirus not previously found in the United States, was implicated in several deaths in New York. By late summer 2002, West Nile virus (WNV) had been identified throughout the eastern and southeastern United States. Following bird migration, the virus began to extend westward, and by April 2003, virus activity had been detected in 46 states and the District of Columbia.

In 2024, 1195 cases of WNV disease were reported in 48 states. Of these, 851 were neuroinvasive. ^[8]

Portals of entry are virus specific. Many viruses are transmitted by humans, though most cases of herpes simplex encephalitis (HSE) are thought to be reactivation of herpes simplex virus (HSV) lying dormant in the trigeminal ganglia. Mosquitoes or ticks inoculate arbovirus, ^[7] and rabies virus is transferred via an infected animal bite or exposure to animal secretions. With some viruses, such as varicella-zoster virus (VZV) and cytomegalovirus (CMV), an immune-compromised state is usually necessary to develop clinically apparent encephalitis.

In general, the virus replicates outside the CNS and gains entry to the CNS either by hematogenous spread or by travel along neural pathways (eg, rabies virus, HSV, VZV). The etiology of slow virus infections, such as those implicated in the measles-related subacute sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML), is poorly understood.

Once across the blood–brain barrier, the virus enters neural cells, with resultant disruption in cell functioning, perivascular congestion, hemorrhage, and a diffuse inflammatory response that disproportionately affects gray matter over white matter. Regional tropism associated with certain viruses is due to neuron cell membrane receptors found only in specific portions of the brain, with more intense focal pathology in these areas. A classic example is the HSV predilection for the inferior and medial temporal lobes.

In contrast to viruses that invade gray matter directly, acute disseminated encephalitis and postinfectious encephalomyelitis (PIE), most commonly due to measles infection and associated with Epstein-Barr virus (EBV) and CMV infections, are immune-mediated processes that result in multifocal demyelination of perivenous white matter.

The cause of encephalitis is usually infectious in nature. Viral agents, such as herpes simplex virus (HSV) types 1 and 2 (the latter much more common in neonates than adults), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), measles virus (PIE and SSPE), mumps virus, and rubella virus, are spread through person-to-person contact. Human herpesvirus 6 may also be a causative agent. ^[9] The CDC has confirmed that West Nile virus (WNV) can be transmitted by means of organ transplantation and via blood transfusions.

Important animal vectors include mosquitoes and ticks, which spread the arbovirus group, and warm-blooded mammals, which are vectors for rabies and lymphocytic choriomeningitis (LCM).

Bacterial pathogens, such as Mycoplasma species and those causing rickettsial disease or catscratch disease, are rare and invariably involve inflammation of the meninges out of proportion to their encephalitic components. Encephalitis due to parasites and fungi other than Toxoplasma gondii are covered elsewhere.

Noninfectious causes include the demyelinating process in acute disseminated encephalitis.

United States statistics

Determining the true incidence of encephalitis is impossible, because reporting policies are neither standardized nor rigorously enforced. In the United States, several thousand cases of viral encephalitis are reported to the CDC each year, ^[5] with an additional 100 cases a year attributed to post-infection encephalitis (PIE). These figures probably represent a fraction of the actual number of cases.

Herpes simplex encephalitis (HSE), the most common cause of sporadic encephalitis in Western countries, is relatively rare; the overall incidence is 0.2 per 100,000, with neonatal herpes simplex virus (HSV) infection occurring in 2–3 per 10,000 live births.

The arbovirus group is the most common cause of episodic encephalitis, with a reported incidence similar to that of HSV. These statistics may be misleading in that most people bitten by arbovirus-infected insects do not develop clinically apparent illness and, of those who do, less than 10% develop overt encephalitis. ^[7]

Arboviruses require an insect vector, which is generally present between June and October. The two most common arboviruses result in (1) St Louis encephalitis, found throughout the United States but principally in urban areas around the Mississippi River, and (2) the geographically misnamed California virus encephalitis (CE)—in particular, LaCross encephalitis (LAC)—which affects children in rural areas in states of the upper Midwest and North East.

Among the other arbovirus-caused encephalitides, the deadliest (and, fortunately, rarest) is eastern equine encephalitis (EEE), which is encountered in New England and surrounding areas. In 2024, 16 cases of EEE were reported in 8 states. ^[10]

Western equine encephalitis (WEE), a milder disease, is most common in rural communities west of the Mississippi River. Powassan virus is the only well-documented arbovirus transmitted by ticks.

Less common causes of viral encephalitis include VZV encephalitis, with an incidence of roughly 1 in 2000 infected persons. Measles produces 2 devastating forms of encephalitis: PIE, which occurs in about 1 in 1000 infected persons, and SSPE, occurring in about 1 in 100,000 infected patients. Rarest in the United States are the 0–3 unrelated annual cases of rabies encephalitis, typically a consequence of the immigration of an infected person from Mexico or Central America during the long incubation period of the rabies virus but prior to the onset of clinically apparent disease.

International statistics

Japanese virus encephalitis (JE), occurring principally in Japan, Southeast Asia, China, and India, is the most common viral encephalitis outside the United States. ^[11]

Age-related differences in incidence

Individuals at the extremes of age are at highest risk, particularly for HSE. Neonatal HSE is a manifestation of disseminated infection type 1 or 2, whereas older infants, children, and adults are much more likely to have localizing CNS infection almost exclusively due to type 1, in a bimodal distribution of patients aged 5–30 years or older than 50 years.

St Louis encephalitis and West Nile encephalitis (WNE) are more common and are most severe in patients older than 60 years; conversely, LAC is more common and is most severe in children younger than 16 years. EEE and WEE disproportionately affect infants while EEE disproportionately affects children and elderly persons.

The prognosis is dependent on the virulence of the virus and the patient’s health status. Extremes of age (< 1 y or > 55 y), immune-compromised status, and preexisting neurologic conditions are associated with poorer outcomes. ^{[12, 13]}

Untreated herpes simplex encephalitis (HSE) has a mortality of 50–75%, and virtually all untreated or late-treatment survivors have long-term motor and mental disabilities. The mortality in treated HSE averages 20%, and the neurologic outcome correlates with the neurological disability present at the time of the first dose of acyclovir or comparable antiviral agents. ^[14] Approximately 40% of survivors have minor-to-major learning disabilities, memory impairment, neuropsychiatric abnormalities, epilepsy, fine-motor-control deficits, and dysarthria. ^[15]

Outcomes in arboviral Japanese encephalitis (JE) and eastern equine encephalitis (EEE) are catastrophic, similar to untreated HSE, with high mortality and severe morbidity, including intellectual disability, hemiplegia, and seizures. ^[16] Other arboviruses cause substantially less morbidity and mortality. For example, St Louis encephalitis and West Nile Encephalitis (WNE) have a mortality rate of 2–20%, the higher rates found in patients older than 60 years. Long-term sequelae with St Louis encephalitis include behavioral disorders, memory loss, and seizures.

Western equine encephalitis (WEE) is associated with few deaths and much less morbidity, although developmental delay, seizure disorder, and paralysis occasionally occur in children, and postencephalitic parkinsonism may occur in adults. CE is typically associated with mild illness, and most patients make a full recovery; however, the minority of patients with severe disease have a 25% chance of focal neurologic dysfunction. Death rates from WEE and LAC are less than 5%.

PIE secondary to measles is associated with a mortality rate approaching 40% of cases, with a high rate of neurologic sequelae in survivors. SSPE is uniformly fatal, although the disease course may last anywhere from several weeks to 10 years.

VZVE has a mortality of 15% in immune-competent patients and virtually 100% in immune-suppressed patients. The mortality for EBV encephalitis is 8%, with substantial morbidity found in approximately 12% of survivors.

Rabies encephalitis and acute disseminated encephalitis are virtually 100% fatal, although there are rare survivors reported in the medical literature.